1. Field
The present invention is concerned with novel tertiary amines, a process for their manufacture, pharmaceutical preparations which contain such compounds and the use of these compounds in the production of pharmaceutical preparations.
2. Description
There has been a long felt need in the medical community for antimycoticly active agents and cholesterol-lowering agent. The subject invention addresses this need.
The subject invention provides compounds of the formula: 
wherein
A1 is C1-C20 alkyl or C3-C20 alkenyl,
A2 is C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C20-alkyl, unsubstituted C1-C20 alkyl, unsubstituted C3-C20 alkenyl, C1-C20 alkyl substituted by R1, CONH2 or CN, or C3-C20 alkenyl substituted by R1, CONH2 or CN, and when A1 is C1-C20 alkyl, A2 can also be OH, and
A3 and A4 are each independently hydrogen or C1-C20 alkyl; or
A1 and A2 together form a C2-C8 alkylene, C4-C8 alkenylene, C6-C8 alkadienylene, R1 substituted C2-C8 alkylene, R1 substituted C4-C8 alkenylene, or R1 substituted C6-C8 alkadienylene group A1-A2,
and in group A1-A2 one or two C atoms can be replaced by one or two groups selected from the group consisting of N atoms and N(C1-C20 alkyl), or
A1 and A3 together form a C2-C8 alkylene, C4-C8 alkenylene, C6-C8 alkadienylene, R1 substituted C2-C8 alkylene, R1 substituted C4-C8 alkenylene, or R1 substituted C6-C8 alkadienylene group A1-A3,
and in group A1-A3 one or two C atoms can be replaced by one or two groups selected from the group consisting of N atoms and N(C1-C20 alkyl);
R1 is OH, oxo, C1-C20 alkyl(O), C1-C20 alkyl(S) or di(C1-C20 alkyl)amino bonded to a saturated C atom of A2, A1-A2 or A1-A3, provided that a C atom substituted by R1 or an unsaturated C atom present in A1, A2, A1-A2 or A1-A3 must be bonded in a position other than the xcex1-position to N(A1A2);
p=1 and L is phenylene, C4-C11 alkylene which has at least 4 C atoms between the two free valencies or C3-C11 alkenylene which has at least 3 C atoms between the two free valencies, and which is bonded to M directly or via O, NH or N(C1-C20 alkyl) or N(C1-C20 alkanoyl), or L is C3-C6 cycloalkylene-C1-C20-alkylene, or
p=0 and L is C6-C11-alkenylene or C6-C11-alkadienylene, bonded to T;
M is thienylene, pyridylene, 1,4-phenylene, 1,4-phenylene substituted by at least one substituent selected from the group consisting of C1-C20 alkyl, halogen, N(R2,R21), CONH2, CN, NO2, CF3, OH, C1-C20 alkyl(O), C1-C20 alkyl(S), 1,2,4-triazol-1-yl and tetrazol-1-yl, or a group of the formula: 
q is 1 or 0;
R2 and R21 are independently H, C1-C20 alkyl, C2-C20 alkenyl, C1-C20 alkanoyl or SO2xe2x80x94(C1-C20 alkyl);
T is CO, CH(R3), C(R4,R5) or Cxe2x95x90NOR6 and, when M is a group M1 and q=0, T can also be SO2;
R3 is OH, F, C1-C20 alkoxy or C1-C20 alkanoyloxy;
R4 is OH and R5 is C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkinyl, cycloalkyl or CF3, or
R4 and R5 together are the group CH2, CH2O or CH2CH2;
R6 is H, C1-C20 alkyl or C2-C20 alkenyl;
Q is C3-C6 cycloalkyl, C(R7,R8), phenyl substituted by at least one substituent selected from the group consisting of C1-C20 alkyl, halogen, N(R9,R10), CONH2, CN, NO2, CF3, 1,2,4-triazol-1-yl and tetrazol-1-yl, or a straight-chain C6-C13 alkyl, C6-C13 alkenyl, C6-C13 alkadienyl or C6-C13 alkatrienyl group Qxe2x80x2 with 0 to 3 methyl substituents, and a group Qxe2x80x2 can be substituted by at least one substituent selected from the group consisting of OH and N(R9,R10),
R7 and R8 are C5-C11-alkyl, C5-C11-alkenyl or C5-C11-alkadienyl, and
R9 and R10 are H, C1-C20 alkyl, C2-C20 alkenyl or C1-C20 alkanoyl, provided that
(a) A2 must not be C1-C20 alkyl or C3-C20 alkenyl, or A1 and A2 together must not be C2-C8 alkylene in a compound of formula I in which T is a group CO or CHOH, L is phenylene or an C4-C11 alkylene or C3-C11 alkenylene group bonded to M directly or via O or N(C1-C20 alkyl), M is 1,4-phenylene or 1,4-phenylene monosubstituted by C1-C20 alkyl, C1-C20 alkyl(O), halogen, CN, NO2 or CF3, and Q is substituted phenyl, C6-C13 alkenyl, C6-C13 alkyl or C6-C13 alkyl substituted by OH,
(b) M must not be pyridylene in a compound of formula I in which A1 and A2 together are C2-C8 alkylene or C2-C8 alkylene substituted by R1, A2 is C1-C20 hydroxyalkyl or A1 and A2 are each C1-C20 alkyl, and
(c) in a compound of formula I in which T is a group C(OH, R51), wherein R51 is C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl or C3-C6 cycloalkyl, M is 1,4-phenylene or substituted 1,4-phenylene and L is an alkylene group bonded to M via a O atom, the alkylene must be a C5-C11 alkylene containing at least 5 C atoms between the 2 free valencies,
and pharmaceutically usable acid addition salts thereof.
Of particular importance are compounds of the formula: 
wherein
A100 is C1-C6 alkyl;
A200 is C3-C6 cycloalkyl, C3-C6 alkenyl, C1-C6 alkyl, C3-C6 cycloalkyl-C13-alkyl;
L100 is C4-C6 alkylene, C3-C6 alkenylene, or C3-C6 cycloalkylene-C1-C13-alkylene;
a is 1;
R100 is O;
M100 is 1,4-phenylene, 1,4-phenylene substituted with at least one substituent selected from the group consisting of halogens,
T100 is Cxe2x95x90O, Cxe2x95x90Nxe2x80x94Oxe2x80x94(C1-C6 alkyl), Cxe2x95x90CH2, C(C1-C6 alkyl, OH); and
Q100 is phenyl substituted with at least one substituent selected from the group consisting of the halogens,
and pharmaceutically salts acid addition salts thereof.
Especially preferred are compounds wherein
A100 is C1-C3 alkyl;
A200 is C3-C6 cycloalkyl, C3-C6 alkenyl;
L100 is C3-C5 alkenylene or C3-C6 cycloalkylene-C1-C3-alkylene;
a is 1;
R100 is O;
M100 is 1,4, phenylene, 1,4 phenylene substituted with at least one fluorine;
T100 is Cxe2x95x90O, Cxe2x95x90Nxe2x80x94Oxe2x80x94(C1-C3 alkyl), Cxe2x95x90CH2, C(C1-C3 alkyl, OH); and
Q100 is phenyl substituted with at least one halogen atom,
and pharmaceutically usable acid addition salts thereof.
And more preferred compounds are wherein
A100 is methyl;
A200 is cyclopropyl or allyl;
L100 is cyclopropylene-methylene or propenylene;
R100 is O;
M100 is 1,4-phenylene or 3 fluoro-1,4-phenylene;
T100 is Cxe2x95x90O or C(CH3)OH; and
Q100 is bromophenyl,
and pharmaceutically usable acid addition salts thereof.
Compounds of the structures: 
and pharmaceutically usuable acid addition salts thereof are favored.
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention, but are not to be construed as limiting.
The invention is concerned with tertiary amines of the formula 
wherein
A1 is alkyl or alkenyl and
A2 is cycloalkyl, cycloalkyl-alkyl or an alkyl or alkenyl group optionally substituted by a group R1, CONH2 or CN and, where A1 is alkyl, A2 can also be OH,
A3 and A4 are hydrogen or alkyl or
A1 and A2 or A3 together form an alkylene, alkenylene or alkadienylene group A1-A2 or A1-A3 with up to 5 C atoms optionally substituted by R1,
and in a group A1-A2 or A1-A3 up to 2 C atoms can be replaced by one (or two) N atom(s) and/or by a N-alkyl group,
R1 is OH, oxo, alkyl(O or S) or dialkylamino bonded to a saturated C atom of A2, A1-A2 or A1-A3, provided that a C atom substituted by R1 or an unsaturated C atom present in A1, A2, A1-A2 or A1-A3 must be bonded in a position other than the xcex1-position to N(A1A2),
p=1 and L is phenylene, or alkylene or alkenylene which has a total of up to 11 C atoms and at least 4 or, respectively, 3 C atoms between the two free valencies and which is bonded to M directly or via O, NH or N(alkyl or alkanoyl) or L is cycloalkylene-alkylene or
p=0 and L is C6-11-alkenylene or C6-11-alkadienylene bonded to T,
M is thienylene, pyridylene, 1,4-phenylene, 1,4-phenylene substituted by one or more substituents from the group of alkyl, halogen, N(R2,R21), CONH2, CN, NO2, CF3, OH, alkyl(O or S), 1,2,4-triazol-1-yl or tetrazol-1-yl or a group of the formula 
Q is 1 or 0,
R2 and R21 are H, alkyl, alkenyl, alkanoyl or SO2-alkyl,
T is CO, CH(R3), C(R4,R5) or Cxe2x95x90NOR6 and, where M is a group M1 and q=0, T can also be SO2,
R3 is OH, F, alkoxy or alkanoyloxy,
R4 is OH and R5 is alkyl, alkenyl, alkynyl, cycloalkyl or CF3 or
R4 and R5 together are the group CH2, CH2O or CH2CH2,
R6 is H, alkyl or alkenyl,
Q is cycloalkyl, C(R7,R8), phenyl substituted by one or more substituents from the group of alkyl, halogen, N(R9,R10), CONH2, CN, NO2, CF3, 1,2,4-triazol-1-yl and tetrazol-1-yl or a straight-chain alkyl, alkenyl, alkadienyl or alkatrienyl group Qxe2x80x2 with 0 to 3 methyl substituents and a total of 6 to 13 C atoms, and a group Qxe2x80x2 can be substituted by OH and/or by N(R9,R10),
R7 and R8 are C5-11-alkyl, C5-11-alkenyl or C5-11-alkadienyl and
R9 and R10 are H, alkyl, alkenyl or alkanoyl, with the provisos that
a) A2 must not be alkyl or alkenyl or A1 and A2 together must not be alkylene in a compound of formula I in which T is a group CO or CHOH, L is phenylene or an alkylene or alkenylene group bonded to M directly or via O or N-alkyl, M is 1,4-phenylene or 1,4-phenylene monosubstituted by alkyl, alkoxy, halogen, CN, NO2 or CF3 and Q is substituted phenyl, an alkenyl group or an alkyl group optionally substituted by OH,
b) M must not be pyridylene in a compound of formula I in which A1 and A2 together signify alkylene or alkylene substituted by R1, A2 is hydroxyalkyl or A1 and A2 are each an alkyl group and
c) in a compound of formula I in which T is a group C(OH, R51), wherein R51 is alkyl, alkenyl, alkynyl or cycloalkyl, M is 1,4-phenylene or substituted 1,4-phenylene and L is an alkylene group bonded to M via a O atom, the alkylene group must contain at least 5 C atoms between the 2 free valencies and a total of up to 11 C atoms,
and acid addition salts thereof.
In the scope of the present invention terms such as xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkadienylxe2x80x9d and xe2x80x9calkatrienylxe2x80x9d alone or in combination such as in cycloalkyl-alkyl denote monovalent and, unless specified otherwise, straight-chain or branched groups with up to 20, especially up to 13, C atoms; further in the case of alkyl, alkenyl and alkadienyl up to 8 C atoms, in the case of alkyl and alkenyl up to 6, especially up to 4, C atoms. Examples for alkyl are methyl, ethyl, propyl, isopropyl, n-, s- and t-butyl, pentyl, hexyl, decyl and dodecyl, for alkanoyl: formyl and acetyl, for alkenyl: vinyl, allyl, propenyl, butenyl, 3-methyl-2-butenyl, 4-methyl-3-pentenyl and undodecenyl, for alkynyl: ethynyl, for alkadienyl: 4-methyl-1,3-pentadienyl; 3,7-dimethyl-2,6-octadienyl and 4,8-dimethyl-3,7-nonadienyl, for alkatrienyl: 4,8-dimethyl-1,3,7-nonatrienyl. xe2x80x9cAlkylenexe2x80x9d, xe2x80x9calkenylenexe2x80x9d and xe2x80x9calkadienylenexe2x80x9d denote the divalent groups corresponding to the monovalent alkyl, alkenyl and, respectively, alkadienyl groups defined above, such as pentylene and 3-methyl-pentylene; propenylene and 2,6-dimethyl-1-hexenylene; 1,5-dimethyl-1,5-hexadienylene; 2,6-dimethyl-1,5-hexadienylene; 2,6-dimethyl-1,5-octadienylene and 3,7-dimethyl-3,7-octadienylene. xe2x80x9cCycloalkylxe2x80x9d and xe2x80x9ccycloalkylenexe2x80x9d alone or in combination preferably contain 3 to 6 C atoms such as e.g. cyclopropyl and cyclohexyl and, respectively, cyclopropylene. Examples of xe2x80x9cthienylenexe2x80x9d and xe2x80x9cpyridylenexe2x80x9d groups are 2,5-thienylene and, respectively, 2,5- or 3,6-pyridylene.
Preferably, A1 stands for methyl, ethyl or allyl; A2 stands for methyl, ethyl, allyl, hydroxy, hydroxypropyl, 2-methoxyethyl, 2-methylsulphanyl-ethyl, carbamoylmethyl, 2-oxo-1-propyl, 2-cyanoethyl, cyclopropyl, cyclopropylmethyl; N(A1,A2) stands for imidazolyl, 4-hydroxy-piperidin-1-yl or 4-dimethylamino-piperidin-1-yl; A3 and A4 stand for hydrogen or methyl; (A1,A2)Nxe2x80x94C(A3,A4)-stands for 1-methylpyrrolidin-2-yl; L stands for (CH2)5O, CHxe2x95x90CHCH2O, 1,4-phenylene, cyclopropylene-methyleneoxy, (CH2)5xe2x80x94NH, CHxe2x95x90CHCH2NH, (CH2)5N(acetyl), CHxe2x95x90CHCH2N(acetyl), CHxe2x95x90C(CH3)CH2CH2CH2CH(CH3), CHxe2x95x90C(CH3)CH2CH2CHxe2x95x90C(CH3), C(CH3)xe2x95x90CHCH2CH2C(CH3)xe2x95x90CH, CHxe2x95x90C(CH3)CH2CH2CHxe2x95x90C(CH3)CH2CH2 or CH2CH2C(CH3)xe2x95x90CHCH2CH2C(CH3)xe2x95x90CH; M stands for 1,4-phenylene which can be monosubstituted by fluorine, OH, NH2, NHCH3, N(CH3)2, NH(CHO), NH(SO2CH3), SCH3 or 1,2,4-triazol-1-yl, substituted by fluorine and methyl or di- or tetrasubstituted by fluorine; T stands for CO, CHOH, SO2, Cxe2x95x90CH2, C(CH2CH2), C(OH, vinyl), CHF, C(OH, CH3), C(OH, CF3), C(OH, cyclopropyl), Cxe2x95x90NOH, Cxe2x95x90NOCH3, Cxe2x95x90NO-tert.butyl or Cxe2x95x90NO-allyl; Q stands for bromophenyl, cyanophenyl, carbamoylphenyl, difluorophenyl, phenyl substituted by F and N(CH3)2, cyclohexyl, 4-methylpentyl, 3-butenyl, 4-methyl-3-pentenyl, 4-methyl-1,3-pentadienyl, 4,8-dimethyl-1,3,7-nonatrienyl, 10-aminodecyl, 10-acetaminodecyl, 2-hydroxy-1,2-(allyl-methyl-amino)dodecyl, 1,2-(allyl-methyl-amino)-1-dodecenyl, 2-hydroxy-4-methyl-3-pentenyl; 4,8-dimethyl-2-hydroxy-3,7-nonadienyl, CH[CH2CHxe2x95x90C(CH3)2]2 or CH[CH2CHxe2x95x90C(CH3)CH2CH2CHxe2x95x90C(CH3)2]2.
As pharmaceutically acceptable acid addition salts there come into consideration salts of compounds I with inorganic and organic acids such as HCl, HBr, H2SO4, HNO3, citric acid, acetic acid, succinic acid, fumaric acid, tartaric acid, methanesulphonic acid and p-toluenesulphonic acid.
The compounds of formula I which contain one or more asymmetric C atoms can be present as enantiomers, as diastereomers or as mixtures thereof, for example, as racemates.
Preferred compounds of formula I are
A) those in which A2 is cycloalkyl or cycloalkyl-alkyl and T is CO, especially the compounds of the formula 
wherein A10 is alkyl, A20 is cycloalkyl or cycloalkyl-alkyl, L0 is alkylene or alkenylene with a total of up to 11 C atoms and at least 4 or, respectively, 3 C atoms between the two free valencies or cycloalkylene-alkylene, M0 is optionally halogenated 1,4-phenylene and Q0 is phenyl substituted by halogen or CN, especially wherein A10 is methyl, A20 is cyclopropyl or cyclopropylmethyl, L0 is n-pentylene, n-propenylene or cyclopropylenemethylene, M0 is unsubstituted or fluorinated 1,4-phenylene and Q0 is phenyl substituted by Br or CN, especially:
(4-bromo-phenyl)-[4-[6-(cyclopropyl-methyl-amino)-hexyloxy]-2-fluoro-phenyl]-methanone,
(E)-(4-bromo-phenyl)-[4-[4-(cyclopropyl-methyl-amino)-but-2-enyloxy]-phenyl]-methanone,
[6-[6-(cyclopropyl-methyl-amino)-hexyloxy]-phenyl]-(4-bromo-phenyl)-methanone,
(E)4-[4-[4-(cyclopropyl-methyl-amino)-but-2-enyloxy]-3-fluoro-benzoyl]-benzonitrile,
(4-bromo-phenyl)-[4-[6-(cyclopropylmethyl-methyl-amino)-hexyloxy]-phenyl]-methanone,
(1RS,2RS)-(4-bromo-phenyl)-[4-[2-[(cyclopropyl-methyl-amino)-methyl]-cyclopropylmethoxy]-phenyl]-methanone,
(1RS,2RS)-(4-bromo-phenyl)-[4-[2-[(cyclopropyl-methyl-amino)-methyl]-cyclopropylmethoxy]-3-fluoro-phenyl]-methanone
as well as the following compounds:
1-[4-[6-(cyclopropylmethyl-methyl-amino)-hexyloxy]-2-fluoro-phenyl]-5-methyl-hex-4-en-1-one,
1-[4-[6-(cyclopropyl-methyl-amino)-hexyloxy]-2-fluoro-phenyl]-5-methyl-hex-4-en-1-one,
(E)-(4-bromo-phenyl)-[4-[4-(cyclopropylmethyl-methyl-amino)-but-2-enyloxy]-phenyl]-methanone,
(E)-4-[4-[4-(cyclopropyl-methyl-amino)-but-2-enyloxy]-3-fluoro-benzoyl]-benzamide
(1RS,2RS)4-[4-[2-[(cyclopropyl-methyl-amino)-methyl]-cyclopropyl-methoxy]-3-fluoro-benzoyl]-benzonitrile,
(1RS,2RS)-(4-bromo-phenyl)-[4-[2-[(cyclopropylmethyl-methyl-amino)-methyl]-cyclopropylmethoxy]-phenyl]-methanone,
(1RS,2RS)-(4-bromo-phenyl)-[4-[2-[(cyclopropyl-methyl-amino)-methyl]-cyclopropylmethoxy]-2-fluoro-phenyl]-methanone,
(1RS,2RS)-[4-[2-[(allyl-cyclopropyl-amino)-methyl]-cyclopropylmethoxy]-phenyl]-(4-bromo-phenyl)-methanone,
(1RS,2RS)-1-[4-[2-[(cyclopropyl-methyl-amino)-methyl]-cyclopropyl-methoxy]-phenyl]-5-methyl-hexan-1-one,
B) those in which T is a group CHOH, CHF, C(R4,R5) or Cxe2x95x90NOR6 and R4, R5 and R6 have the same significance as given above, especially in which T is a group C(OH, alkyl), C(OH, alkenyl), Cxe2x95x90CH2 or Cxe2x95x90NO-alkyl, especially the compounds of the formula 
wherein A10 is alkyl, A21 is alkenyl, L1 is alkylene or alkenylene with a total of up to 11 C atoms and at least 4 or, respectively, 3 C atoms between the two free valencies, M0 is optionally halogenated 1,4-phenylene, T1 is a group C(OH, alkyl), C(OH, alkenyl), Cxe2x95x90CH2 or Cxe2x95x90NO-alkyl and Q2 is halophenyl or alkenyl with 0 to 3 methyl substituents and a total of 6 to 13 C atoms, especially wherein A10 is methyl, A21 is allyl, L1 is n-pentylene or n-propenylene, M0 is unsubstituted or fluorinated 1,4-phenylene and Q2 is bromophenyl or 4-methylpent-3-enyl, especially:
(E)-(RS)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-phenyl]-(4-bromo-phenyl)-ethanol,
(E)-(RS)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-phenyl]-1-(4-bromo-phenyl)-prop-2-en-1-ol,
(E)-allyl-[4-[4-[1-(4-bromo-phenyl)-vinyl]-phenoxy]-but-2-enyl]-methyl-amine,
(RS)-1-[4-[6-(allyl-methyl-amino)-hexyloxy]-2-fluoro-phenyl]-1-(4-bromo-phenyl)-ethanol,
(E)-(RS)-2-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-phenyl]-6-methyl-hept-5-en-2-ol
as well as the following compounds:
(E)-(RS)-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-phenyl]-(4-bromo-phenyl)-cyclopropyl-methanol,
(E)-(RS)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-phenyl]-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethanol,
(RS)-1-[4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl]-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethanol,
(E)-allyl-[4-[4-[1-(4-bromo-phenyl)-cyclopropyl]-phenoxy]-but-2-enyl]-methyl-amine,
(E)-(R or S)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-phenyl]-(4-bromo-phenyl)-ethanol,
(E)-(S or R)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-phenyl]-(4-bromo-phenyl)-ethanol,
allyl-[6-[4-[1-(4-bromo-phenyl)-vinyl]-3-fluoro-phenoxy]-hexyl]-methyl-amine,
(E)-(RS)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-(4-bromo-phenyl)-prop-2-en-1-ol,
(RS)-1-[4-[(allyl-methyl-amino)-methyl]-biphenyl-4-yl]-1-(4-bromo-phenyl)-ethanol,
(RS)-5-[6-(allyl-methyl-amino)-hexyloxy]-2-[1-(4-bromo-phenyl)-1-hydroxy-allyl]-phenol,
(RS)-1-[4-[6-(allyl-methyl-amino)-hexyloxy]-2-amino-phenyl]-1-(4-bromo-phenyl)-prop-2-en-1-ol,
(RS)-allyl-[4xe2x80x2-[(4-bromo-phenyl)-fluoro-methyl]-biphenyl-4-ylmethyl]-methyl-amine,
(E)- and/or (Z)-[4-[(E)-4-(allyl-methyl-amino)-but-2-enyloxy]-phenyl]-(4-bromo-phenyl)-methanone O-methyl oxime,
(E)- and/or (Z)-[4-[(E)-4-(allyl-methyl-amino)-but-2-enyloxy]-phenyl]-(4-bromo-phenyl)-methanone oxime,
(E)- and/or (Z)-[4-[(E)-4-allyl-methyl-amino)-but-2-enyloxy]-phenyl-(4-bromo-phenyl)-methanone O-tert-butyl oxime,
(E)- and/or (Z)-[4-[(E)-4-(allyl-methyl-amino)-but-2-enyloxy]-phenyl]-(4-bromo-phenyl)-methanone O-allyl oxime,
(E)- and/or (Z)-[4-[6-(allyl-methyl-amino)-hexyloxy]-2-fluoro-phenyl]-(4-bromo-phenyl)-methanone oxime,
C) those in which M is 1,4-phenylene optionally substituted by alkyl, halogen, NH2, mono- or di-alkylated amino, alkanoylamino, OH, alkyl(O or S) or 1,2,4-triazol-1-yl, especially in which M is 1,4-phenylene substituted by NH2, mono- or di-alkylated amino, OH, S-alkyl or two halogen atoms, especially the compounds of the formula 
wherein A10 is alkyl, A21 is alkenyl, L2 is alkylene with up to 11 C atoms and at least 4 C atoms between the two free valencies, M2 is 1,4-phenylene substituted by NH2, mono- or dialkylated amino, OH, S-alkyl or two halogen atoms and Q3 is halogenated phenyl, especially wherein A10 is methyl, A21 is allyl, L2 is n-pentylene, M2 is 1,4-phenylene substituted by NH2, NHCH3, N(CH3)2, OH, SCH3 or by two F atoms and Q3 is bromophenyl, especially:
(E)-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-2,5-difluoro-phenyl]-(4-bromo-phenyl)-methanone,
[4-[6-(allyl-methyl-amino)-hexyloxy]-2-methylsulphanyl-phenyl]-(4-bromo-phenyl)-methanone,
[4-[6-(allyl-methyl-amino)-hexyloxy]-2-methylamino-phenyl]-(4-bromo-phenyl)-methanone,
[4-[6-(allyl-methyl-amino)-hexyloxy]-2-dimethylamino-phenyl]-(4-bromo-phenyl)-methanone,
[4-[6-(allyl-methyl-amino)-hexyloxy]-2-hydroxy-phenyl]-(4-bromo-phenyl)-methanone,
[2-amino-4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl]-(4-bromo-phenyl)-methanone
as well as the following compounds:
(E)-(4-bromo-phenyl)-[2,5-difluoro-4-(4-dimethylamino-but-2-enyloxy]-methanone,
[4-[6-(allyl-methyl-amino)-hexyloxy]-2,5-difluoro-phenyl]-(4-bromo-phenyl)-methanone,
(E)-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-2,5-difluoro-phenyl]-(2,4-difluoro-phenyl)-methanone,
(E)-[2,5-difluoro-4-(4-dimethylamino-but-2-enyloxy)-phenyl]-(2,4-difluoro-phenyl)-methanone,
[4-[6-(allyl-methyl-amino)-hexyloxy]-2,5-difluoro-phenyl]-(2,4-difluoro-phenyl)-methanone,
(2,4-difluoro-phenyl)-[4-(6-dimethylamino-hexyloxy)-2,5-difluoro-phenyl]methanone,
(E)-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-2,3,5,6-tetrafluoro-phenyl]-(4-bromo-phenyl]-methanone,
(E)-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-2-methyl-phenyl]-(4-bromo-phenyl)-methanone,
(E)-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-2-methylsulphanyl-phenyl]-(4-bromo-phenyl)-methanone,
(E)-N-[11-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-1-oxo-undecyl]-acetamide,
(E)-[4-(4-allyl-methyl-amino-but-2-enyloxy)-2-hydroxy-phenyl]-(4-bromo-phenyl)-methanone,
(E)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-11-amino-undecan-1-one,
(E)-1-[4-[(E)-4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-2-[(E)-3,7-dimethyl-octa-2,6-dienyl]-5,9-dimethyl-deca-4,8-dien-1-one,
(E)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-5-methyl-2-(3-methyl-but-2-enyl)-hex-4-en-1-one,
(E)-(RS)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-3-hydroxy-5-methyl-hex-4-en-1-one,
(E)-(RS)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-2-fluoro-phenyl]-3-hydroxy-5-methyl-hex-4-en-1-one,
(E)-(RS)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-phenyl]-3-hydroxy-5-methyl-hex-4-en-1-one,
(E)-(RS)-1-[4-[(E)-4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-3-hydroxy-5,9-dimethyl-deca-4,8-dien-1-one,
(E)-(RS)-13-(allyl-methyl-amino)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-3-hydroxy-tridecan-1-one,
(E)-1-[4-[(E)-4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-5-methyl-hexa-2,4-dien-1-one,
(E)-13-(allyl-methyl-amino)-1-[4-[(E)-4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-tridec-2-en-1-one,
(E)-1-[4-[(E)-4-(allyl-methyl-amino)-but-2-enyloxy]-2-fluoro-phenyl]-5-methyl-hexa-2,4-dien-1-one,
(E)-1-[4-[(E)-4-(allyl-methyl-amino)-but-2-enyloxy]-phenyl]-5-methyl-hexa-2,4-dien-1-one,
(2E,4E)-1-[4-[(E)-4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-5,9-dimethyl-deca-2,4,8-trien-1-one,
[4-[6-(allyl-methyl-amino)-hexyloxy]-2-1H-[1,2,4]triazol-1-yl-phenyl]-(4-bromo-phenyl)-methanone,
1-[4-[6-(allyl-methyl-amino)-hexyloxy]-2-methylamino-pheny]-4-methyl-hex-5-en-1-one,
(E)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-2-methylsulphanyl-phenyl]-5-methyl-hex-4-en-1-one,
N-[5-[6-(allyl-methyl-amino)-hexyloxy]-2-(4-bromo-benzoyl)-phenyl]-methanesulphonamide,
(4-bromo-phenyl)-(4xe2x80x2-dimethylaminomethyl-3-hydroxy-biphenyl-4-yl)-methanone,
N-[5-[6-(allyl-methyl-amino)-hexyloxy]-2-(4-bromo-benzoyl)-phenyl]-formamide,
D) those in which L is an alkylene or alkenylene group which has a total of up to 11 C atoms and at least 4 or, respectively, 3 C atoms between the two free valencies and which is bonded to M via MH or N-alkanoyl, especially the compounds of the formula 
wherein A10 is alkyl, A21 is alkenyl, L1 is alkylene or alkenylene with a total of up to 11 C atoms and at least 4 or, respectively, 3 C atoms between the two free valencies, M3 is halogenated 1,4-phenylene and Q3 is halogenated phenyl, especially wherein A10 is methyl, A21 is allyl, L1 is n-pentylene or n-propenylene, M3 is fluorophenylene and Q3 is bromophenyl, especially:
(E)-[4-[4-(allyl-methyl-amino)-but-2-enylamino]-3-fluoro-phenyl]-(4-bromo-phenyl)-methanone,
[4-[6-(allyl-methyl-amino)-hexylamino]-3-fluoro-phenyl]-(4-bromo-phenyl)-methanone
as well as the following compounds:
(E)-N-[4-(allyl-methyl-amino)-but-2-enyl]-N-[4-(4-bromo-benzoyl)-2-fluoro-phenyl]-acetamide,
N-[6-(allyl-methyl-amino)-hexyl]-N-[4-(4-bromobenzoyl)-2-fluoro-phenyl]-acetamide,
E) those in which M is a group of the formula 
xe2x80x83and q is 1 or 0, especially in which M and T together form the piperidin-1-ylsulphonyl group, especially the compounds of the formula 
wherein A10 is alkyl, A21 is alkenyl, L2 is alkylene with up to 11 C atoms and at least 4 C atoms between the two free valencies and Q3 is halogenated phenyl, especially wherein A10 is methyl, A21 is allyl, L2 is n-pentylene and Q3 is bromophenyl, especially
allyl-[6-[1-(4-bromo-phenylsulphonyl)-piperidin-4-yloxy]-hexyl]-methyl-amine
and the compounds:
[4-[6-(allyl-methyl-amino)-hexyloxy]-piperidin-1-yl]-1-(4-bromo-phenyl)methanone,
2-[4-[6-(allyl-methyl-amino)-hexyloxy]-piperidin-1-yl]-1-(4-bromo-phenyl)-ethanone,
F) those in which A1 is alkyl and A2 is OH or alkyl optionally substituted by a group R1, CONH2 or CN or
A1 and A2 or A3 together form an alkylene, alkenylene or alkadienylene group
A1-A2 or A1-A3 which has up to 5 C atoms and which is optionally substituted by R1,
and a C atom in a group A1-A2 or A1-A3 can be replaced by a N atom and R1 is OH, oxo, alkyl(O or S) or dialkylamino bonded to a saturated C atom of A2, A1-A2 or A1-A3,
provided that a C atom substituted by R1 or an unsaturated C atom present in A2, A1-A2 or A1-A3 must be bonded in a position other than the xcex1-position to N(A1A2),
especially the compounds in which A1 and A2 together signify alkylene which has up to 5 C atoms and which is substituted by OH as well as the compounds of the formula 
wherein A1 and A2 together signify an alkylene group which has up to 5 C atoms and which is substituted by OH, L3 is alkenylene with a total of up to 11 C atoms and at least 3 C atoms between the two free valencies and Q3 is halogenated phenyl, especially wherein A1 and A2 together are 4-hydroxy-piperidin-1-yl, L3 is n-propenylene and Q3 is bromophenyl, especially:
(E)-(4-bromo-phenyl)-[4-[4-(4-hydroxy-piperidin-1-yl)-but-2-enyloxy]-phenyl]-methanone
as well as the following compounds:
cyclohexyl p-[[(E)-4-(dimethylamino)-2-butenyl]oxy]phenyl ketone,
(E)-[[4-[4-(4-bromo-benzoyl)-phenoxy]-but-2-enyl]-methyl-amino]-acetonitrile,
(E)-3-[[4-[4-(4-bromo-benzoyl)-phenoxy]-but-2-enyl]-methyl-amino]-propionitrile,
(E)-(4-bromo-phenyl)-[4-[4-(4-dimethylamino-piperidin-1-yl)-but-2-enyloxy]-phenyl]-methanone,
(4-bromo-phenyl)-[4-[6-(hydroxy-methyl-amino)-hexyloxy]-phenyl]-methanone,
(E)-(4-bromo-phenyl)-[4-[4-(hydroxy-methyl-amino)-but-2-enyloxy]-phenyl]-methanone,
(E)-(4-bromo-phenyl)-[4-[4-[(2-methoxy-ethyl)-methyl-amino]-but-2-enyloxy]-phenyl]-methanone,
(E)-(4-bromo-phenyl)-[4-[4-[methyl-(2-methylsulphanyl-ethyl)-amino]-but-2-enyloxy]-phenyl]-methanone,
(E)-(4-bromo-phenyl)-[4-(4-imidazol-1-yl-but-2-enyloxy)-phenyl]-methanone,
(4-bromo-phenyl)-[4-(6-imidazol-1-yl-hexyloxy)-phenyl]-methanone,
(4-bromo-phenyl)-[4-[6-[(3-hydroxy-propyl)-methyl-amino]-hexyloxy]-phenyl]-methanone,
1-[[6-[4-(4-bromo-benzoyl)-phenoxy]-hexyl]-methyl-amino]-propan-2-one,
(E)-2-[[4-[4-(4-bromo-benzoyl)-phenoxy]-but-2-enyl]-methyl-amino]-acetamide,
(xc2x1)(4-bromo-phenyl)-[4xe2x80x2-(1-methylpyrrolidin-2-yl)-biphenyl-4-yl]-methanone,
G) those in which p=0 and L is C6-11-alkenylene or C6-11-alkadienylene bonded to T, especially the compounds of the formula 
wherein A10 is alkyl, A21 is alkenyl, L4 is C6-11-alkadienylene and Q4 is an alkenyl group with 0 to 3 methyl substituents and a total of 6 to 13 C atoms, especially wherein A10 is methyl, A21 is allyl, L4 is dimethylocta-dienylene and Q4 is 4-methyl-3-pentenyl, especially:
(9E,13E)-15-(allyl-methyl-amino)-2,9,13-trimethyl-pentadeca-2,9,13-trien-6-one
as well as the following compounds:
(4E,8E)-10-(allyl-methyl-amino)-1-(4-bromo-phenyl)-4,8-dimethyl-deca-4,8-dien-1-one,
(4E,8E)-1-(4-bromo-phenyl)-10-dimethylamino-4,8-dimethyl-deca-4,8-dien-1-one,
(7E,11E)-13-(allyl-methyl-amino)-2,7,11-trimethyl-trideca-2,7,11-trien-6-one,
(7E,11E)- and (7Z,11E)-13-(allyl-methyl-amino)-2,7,11-trimethyl-trideca-2,7,11-trien-6-one,
(2E,6E)-8-(allyl-methyl-amino)-1-(4-bromo-phenyl)-2,6-dimethyl-octa-2,6-dien-1-one,
(7E,11E)-13-(allyl-methyl-amino)-7,11-dimethyl-trideca-1,7,11-trien-6-one,
(2E,6E)-(RS)-8-(allyl-methyl-amino)-1-(4-bromo-phenyl)-2,6-dimethyl-octa-2,6-dien-1-ol,
(E)-(RS)-8-(allyl-methyl-amino)-1-(4-bromo-phenyl)-2,6-dimethyl-oct-6-en-1-one,
(2E,6E)-(RS)-10-(allyl-methyl-amino)-1-(4-bromo-phenyl)-3,7-dimethyl-deca-2,6-dien-1-ol,
(2E,6E)-(RS)-8-(allyl-methyl-amino)-1-(4-bromo-phenyl)-3,7-dimethyl-octa-2,6-dien-1-ol,
(2E,6E)-10-(allyl-methyl-amino)-1-(4-bromo-phenyl)-3,7-dimethyl-deca-2,6-dien-1-one,
(2E,6E)-8-(allyl-methyl-amino)-1-(4-bromo-phenyl)-3,7-dimethyl-octa-2,6-dien-1-one,
H) those in which M is thienylene or pyridylene, especially the following:
(E)-1-[6-[6-(allyl-methyl-amino)-hexyloxy]-pyridin-3-yl]-5-methyl-hexa-2,4-dien-1-one,
6-[6-(allyl-methyl-amino)-hexyloxy]-pyridin-3-yl]-(4-bromo-phenyl)-methanone,
(E)-[6-[4-(allyl-methyl-amino)-but-2-enyloxy]-pyridin-3-yl]-(4-bromo-phenyl)-methanone,
[5-[6-(allyl-methyl-amino)-hexyloxy]-pyridin-2-yl]-(4-bromo-phenyl)-methanone,
5-(4-[(allyl-methylamino)-methyl]-phenyl)-thiophen-2-yl)-(4-bromophenyl)-methanone,
5-(4-[dimethylamino)-methyl]-phenyl)-thiophen-2-yl)-(4-bromophenyl)-methanone,
5-(4-[(allyl-methylamino)-methyl]-phenyl)-thiophen-2-yl)-(4-(2,4-difluorophenyl))-methanone,
(2-dimethylamino-4-fluoro-phenyl)-[5-(4-dimethylaminomethyl-phenyl)-thiophen-2-yl]-methanone,
I) those in which L is cycloalkylene-alkylene bonded to M via an O atom, especially
(1RS,2RS)-(4-bromo-phenyl)-[4-[2-[(ethyl-methyl-amino)-methyl]-cyclopropylmethoxy]-phenyl]-methanone,
(1RS,2RS)-[4-[2-[(allyl-methyl-amino)-methyl]-cyclopropylmethoxy]-phenyl]-(4-bromo-phenyl)-methanone.
The invention is also concerned with a process for the manufacture of the compounds of formula I. This process comprises
a) reacting a bromide of the formula 
with an amine HN(A1,A2),
b) methylating an amine of the formula 
wherein A has the same significance as A2,
c) reacting an amine of formula III, wherein A has the same significance as A1, with a halide of the formula Hal-A0, wherein Hal is halogen and A0 is cycloalkyl-alkyl or alkyl or alkenyl substituted by a group R1, CONH2 or CN,
d) reacting an ethanone of the formula 
wherein M4 stands for 1,4-phenylene, which can be substituted as given above for a 1,4-phenylene group M, or for thienylene or pyridylene,
with a halide of the formula
Hal-R7
to give a ketone of formula I in which T and Q together are a group C(O)C(R7)2 and R7 has the same significance as in formula I,
e) reacting an ethanone of formula IV with an aldehyde of the formula
HC(O)Qxe2x80x3
wherein Qxe2x80x3 is a straight-chain alkyl, alkenyl or alkadienyl group with 0 to 3 methyl substituents and a total of 4 to 11 C atoms,
f) reacting a xcex2-hydroxyketone of the formula 
wherein M5 stands for 1,4-phenylene, which can be substituted as given above for a 1,4-phenylene group M, and Q5 is a divalent group corresponding to one of the above monovalent groups Qxe2x80x3,
with an amine HN(R9,R10),
g) reacting an aminoalcohol of the formula 
wherein L5 is alkylene or alkenylene with a total of up to 11 C atoms and at least 4 or, respectively, 3 C atoms between the two free valencies or cycloalkylene-alkylene,
with a compound of the formula
HOxe2x80x94M6xe2x80x94Txe2x80x94Q,
wherein M6 stands for 1,4-phenylene, which can be substituted as given above, or for thienylene,
h) reacting an aminoalcohol of formula VI with a chloride of the formula 
i) reacting an acid addition salt of an amine of the formula 
wherein A10 is alkyl, A22 is cycloalkyl, cycloalkyl-alkyl or an alkyl group optionally substituted by a group R10 or CN,
A30 and A4 are hydrogen or alkyl or
A10 and A22 or A30 together form an alkylene group optionally substituted by R11, and a C atom in such an alkylene group can be replaced by N-alkyl,
R11 is oxo, alkyl (O or S) or dialkylamino and
L6 is phenylene or alkylene which has a total of up to 11 C atoms and at least 4 C atoms between the two free valencies and which is bonded to the phenyl ring directly or via O or N-alkyl,
with an acid chloride of the formula
ClC(O)xe2x80x94Q6
wherein Q6 is cycloalkyl, C(R70,R80), phenyl substituted by one or more substituents from the group of alkyl, halogen, dialkylamino, CN, NO2, CF3, 1,2,4-triazol-1-yl and tetrazol-1-yl or a straight-chain alkyl group with 0 to 3 methyl substituents and a total of 6 to 13 C atoms and R70 and R80 stand for C5-11-alkyl,
j) reacting a diamine of the formula 
with a halide of the formula
ClS(O)2xe2x80x94Q, ClC(O)xe2x80x94Q or BrCH2C(O)xe2x80x94Q,
k) reacting an aldehyde of the formula 
with an agent which introduces the group Q, and Q is cycloalkyl, C(R7,R8), phenyl substituted by one or more substituents from the group of alkyl, halogen, N(R90,R100), CN, NO2, CF3, 1,2,4-triazol-1-yl and tetrazol-1-yl or a straight-chain alkyl, alkenyl, alkadienyl or alkatrienyl group Q10 with 0 to 3 methyl substituents and a total of 6 to 13 C atoms, and a group Q10 can be substituted by N(R90,R100) and R90 and R100 are alkyl or alkenyl,
l) if desired, functionally modifying reactive groups present in a compound of formula I and
m) if desired, converting an amine of formula I into a physiologically compatible acid addition salt or converting an acid addition salt of a compound of formula I into the amine of formula I.
This process can be carried out in a manner known per se. Thus, reaction a) of a bromide 11 with an amine HN(A1,A2) can be performed
1. in a solvent such as an alcohol, e.g. ethanol, or in acetone, in the presence of a base, e.g. potassium carbonate, at an elevated temperature,
2. in dimethylacetamide (DMA) at room temperature or while cooling or
3. in the presence of NaH in a solvent such as DMF while heating.
The methylation of an amine III in which A has the same significance as A2 in formula I can be carried out in the presence of NaHPO4 in a solvent such as an ether, e.g. dioxan, using formaldehyde while heating.
The reaction of an amine III in which A has the same significance as A1 in formula I with a cycloalkyl-alkyl halide Hal-A0, e.g. a bromide, can be performed in the presence of a base such as diisopropylethylamine in a solvent such as DMA while heating.
The reaction of an ethanone IV with a halide Hal-R7 and/or Hal-R8 leads to the corresponding aminoketone I in which T stands for CO and Q stands for the group C(R7,R7), C(R8,R8) and/or C(R7,R8). The ethanone IV can be reacted firstly with a solution of lithium hexamethyldisilazide (prepared from hexamethyl-disilazane and butyllithium) in THF and then with a solution of the halide, e.g. the bromide, of the formula Hal-R7 and/or Hal-R8 in a solvent such as an ether, e.g. THF, at a low temperature.
Depending on whether M4 in an ethanone IV stands for thienylene or optionally substituted phenylene or for pyridylene, the reaction e) of the ethanone IV with an aldehyde HC(O)Qxe2x80x3 leads to a ketone I in which Txe2x80x94Q stands for C(O)CHxe2x95x90CHxe2x80x94Qxe2x80x3 or to a O-hydroxyketone I in which Txe2x80x94Q stands for C(O)CH2CH(OH)Qxe2x80x3. The ethanone IV can be reacted firstly with a solution of lithium diisopropylamide (prepared from diisopropylamine and butyl-lithium) in THF and then with a solution of the aldehyde HC(O)Qxe2x80x3 in THF at a low temperature.
Process variant f) leads to a xcex2-hydroxyketone I in which Txe2x80x94Q is a group
C(O)CH2CH(OH)Q5xe2x80x94N(R9,R10).
This variant can be carried out by reacting a solution of a bromide in DMA with an amine HN(R9,R10) while cooling.
Reaction g) of an aminoalcohol VI with a compound of the formula HOxe2x80x94M6xe2x80x94Txe2x80x94Q leads to an aminoether I in which Lxe2x80x94M is a group L5xe2x80x94Oxe2x80x94M6 in which L5 and M6 are as defined above. It can be performed by treating triphenylphosphine, the compound HOxe2x80x94M6xe2x80x94Txe2x80x94Q and the aminoalcohol VI with diethyl azodicarboxylate in a solvent such as an ether, e.g. THF.
Reaction h) of an aminoalcohol VI with a chloride VII leads to an ether I in which Lxe2x80x94M is a group L5xe2x80x94O-pyridylene. It can be carried out in the presence of a base such as KOH and K2CO3 in the presence of a crown ether such as dicyclohexano-[18]-crown-6 in a solvent such as toluene while heating.
Reaction i) of an acid addition salt of the amine VII with an acid chloride ClC(O)xe2x80x94Q6 leads to the corresponding aminoketone I in which Txe2x80x94Q stands for C(O)xe2x80x94Q6. It can be performed in the presence of aluminium chloride in carbon disulphide while heating.
Reaction j) of a diamine IX with a halide ClS(O)2xe2x80x94Q, ClC(O)xe2x80x94Q or BrCH2C(O)xe2x80x94Q leads to the corresponding amine I in which Txe2x80x94Q stands for S(O)2xe2x80x94Q, C(O)xe2x80x94Q or, respectively, CH2C(O)xe2x80x94Q. It can be carried out in a solvent such as methylene chloride in the presence of di-isopropyl-ethylamine (Hxc3xcnig base).
Process variant k) can be a Grignard reaction between an aldehyde X and a halide such as Qxe2x80x94MgBr. Where Q is optionally substituted phenyl, a halide such as Qxe2x80x94Br in THF can firstly be reacted with butyllithium in hexane and the resulting compound Lixe2x80x94Q can be reacted with an aldehyde X at a low temperature such as about xe2x88x9278xc2x0 C. to give the corresponding ketone I.
The following can be mentioned as functional transformations of reactive groups present in a compound I:
a) The transformation of a cyano group which is present as a substituent on an alkyl group A2 and/or a phenyl group Q into the carbamoyl group can be carried out using a hydrogen peroxide solution in the presence of potassium carbonate in DMSO at about 0xc2x0 C.
b) The hydrolysis of an alkanoylamino group which is present as a substituent on a group Qxe2x80x2 to the amino group can be effected using hydrochloric acid in ethanol.
c) The dehydration of a xcex2-hydroxyketone I in which T stands for C(O) and Q is a hydroxylated group Qxe2x80x2 in the xcex2-position to C(O) to the corresponding ketone I in which Q is an unsaturated group Qxe2x80x2 in the xcex1-position to C(O) can be carried out using p-toluenesulphonic acid in toluene.
d) An amide I in which L is bonded to M via N(alkanoyl) can be converted into the corresponding amine I in which L is bonded to M via NH using a solution of KOH in ethanol.
e) A group CHxe2x95x90CH which is present in L and which is in the xcex1-position to the carbonyl group T in a ketone I in which p=0, the group Txe2x80x94Q is substituted benzoyl and L is alkenylene or alkadienylene can be selectively hydrogenated to CH2CH2. The hydrogenation can be carried out in benzene with a phase transfer catalyst such as tricaprylmethylammonium chloride in the presence of an aqueous solution of sodium hydrogen carbonate and sodium dithionite.
f) A fluorine atom in a benzophenone I in which Q is substituted phenyl and the phenylene group M in the o-position to the carbonyl group T is substituted by fluorine can be
1) converted into the amino group by reaction with methoxybenzylamine in the presence of a base such as potassium carbonate in toluene and subsequent reaction with trifluoroacetic acid,
2) converted into an alkylated or alkenylated amino group or into a 1,2,4-triazol-1-yl or tetrazol-1-yl group by reaction in DMA with an appropriate amine in ethanol or
3) converted into the corresponding alkoxy group or alkylthio group by reaction with a sodium alkanolate or a sodium thioalkanolate in methanol or in tetrahydrofuran.
g) An alkoxy substituent in group M can be converted into the hydroxy group by ether cleavage using aqueous acetic acid/HBr solution.
h) The amino group in a compound I in which M is aminophenylene can be converted into the alkylsulphonylamino group by reaction in methylene chloride with an alkylsulphonyl chloride. The amino group can be converted into the formylamino group using formic acid and formamide.
i) A ketone I in which T is carbonyl can be converted in a manner known per se into the corresponding alcohol in which T is a group [alkyl, alkenyl, alkynyl or cycloalkyl]xe2x80x94C(OH). Thus, in order to convert the carbonyl group into the C(CH3)OH group, the ketone I can be reacted with LiCH3/CeCl3 in THF at about xe2x88x9278xc2x0 C. and in order to convert the carbonyl group into an alkenyl-C(OH) group the ketone I can be reacted with a solution of an alkenylmagnesium halide at about 0xc2x0 C. in THF/ether.
j) An oxime I in which T stands for Cxe2x95x90N(OR6) can be obtained from an acid addition salt of a ketone I in which T is carbonyl by reaction with H2N(OR6) in the presence of sodium acetate in ethanol while heating.
k) An alcohol I in which T is the CH(OH) group can be fluorinated to the fluoride I in which T is the CHF group using diethylamino-sulphur trifluoride in methylene chloride at about xe2x88x9278xc2x0 C. or can be oxidized to the ketone in which T is C(O) using manganese(IV) oxide in the presence of sodium carbonate.
The starting materials II to X used in the above process and the educts required for their preparation are known or can be prepared in analogy to structurally related compounds or in a manner known per se as described in the following Examples.
Thus, a bromide II in which T stands for C(O) and L is bonded to an optionally substituted phenyl group M via a O atom is prepared starting from an ether H3Cxe2x80x94Oxe2x80x94M and an acid chloride ClC(O)xe2x80x94Q via the ether H3Cxe2x80x94Oxe2x80x94Mxe2x80x94C(O)xe2x80x94Q and the corresponding phenol HOxe2x80x94Mxe2x80x94C(O)xe2x80x94Q and reaction of this phenol with a dibromide BrCH2xe2x80x94Lxe2x80x94Br. Bromides II in which T stands for C(OH, alkyl), Cxe2x95x90CH2 or C(CH2CH2) can be prepared analogously via the corresponding phenols HOxe2x80x94Mxe2x80x94Txe2x80x94Q.
A bromide II in which T stands for C(O) and L is bonded to an optionally substituted phenyl group M via a N(alkanoyl) group can be prepared starting from a bromide of the formula alkanoyl-NHxe2x80x94Mxe2x80x94Br and from a compound of the formula N(CH3, OCH3)C(O)xe2x80x94Q via the compound of the formula alkanoyl-NHxe2x80x94Mxe2x80x94C(O)xe2x80x94Q and reaction of this compound with a dibromide BrCH2xe2x80x94Lxe2x80x94Br.
A compound II in which L is phenylene bonded to a thienylene group M is obtained from bromotoluene and bromothiophene via tolyl-thiophene and tolyl-thienylene-C(O)xe2x80x94Q.
In general, a bromide II can be prepared from the corresponding tetrahydropyranyl ether by reaction with triphenylphosphine dibromide in methylene chloride at about xe2x88x9250xc2x0 C. while cooling, preferably to xe2x88x9250 to 0xc2x0 C.
For the preparation of a starting amine III in which A3 and A4 stand for H, a corresponding bromide II can be converted with a trifluoroacetamide F3Cxe2x80x94C(O)xe2x80x94NHxe2x80x94A into F3Cxe2x80x94C(O)xe2x80x94N(A)xe2x80x94CH2xe2x80x94Lxe2x80x94(M)pxe2x80x94Txe2x80x94Q and the trifluoroacetyl group can be cleaved off hydrolytically from the latter.
An amine starting material III for process variant c) is obtained from the corresponding bromide II via the corresponding azide and the compounds F3Cxe2x80x94C(O)xe2x80x94NHxe2x80x94CH2xe2x80x94Lxe2x80x94(M)pxe2x80x94Txe2x80x94Q and F3Cxe2x80x94C(O)xe2x80x94N(A)xe2x80x94CH2xe2x80x94Lxe2x80x94(M)pxe2x80x94Txe2x80x94Q.
Ethanones IV in which A3 and A4 stand for H are obtained by reacting a bromide BrCH2xe2x80x94Lxe2x80x94M4xe2x80x94C(O)xe2x80x94CH3 with an amine (A1,A2)NH in DMA.
A xcex2-hydroxyketone V can be prepared from the corresponding ethanone IV and an aldehyde HC(O)xe2x80x94Q5xe2x80x94Br.
An aminoalcohol VI in which A3 and A4 stand for H and L5 stands for cycloalkylene-alkylene can be obtained from a diester of the formula alkyl-Oxe2x80x94C(O)-cycloalkylene-C(O)O-alkyl via A2xe2x80x94NHxe2x80x94C(O)-cycloalkylene-C(O)O-alkyl and via (A1,A2)xe2x80x94Nxe2x80x94C(O)-cycloalkylene-COO-alkyl and reduction of this amidoester to the aminoalcohol VI: (A1,A2)Nxe2x80x94CH2-cycloalkylene-CH2OH.
A chloride VII in which T stands for C(O) is obtained from the corresponding chloropyridinecarboxylic acid via chloro-N-methoxy-N-methylpyridinecarboxamide.
An amine VIII in which A10 and A22 together form an alkylene group can be prepared starting from a bromide Brxe2x80x94L6-C6H5. This can be converted e.g. with 5-methoxy-2H-3,4-dihydropyrrole into the 2H-3,4-dihydropyrrole which is substituted by xe2x80x94L6-C6H5 in the 5-position, the latter can be hydrogenated to the pyrrolidine which is correspondingly substituted in the 2-position and this can be methylated to the compound VIII in which (A10,A22)NC(A30,A4) is N-methyl-2-pyrrolidinyl.
A diamine of formula IX in which A3 and A4 stand for H and L is alkenylene bonded to the piperidine ring via O is obtained from tert-butyl 4-hydroxy-piperidine-1-carboxylate via the piperidine which is substituted by a group Br-alkylene-Oxe2x80x94 in the 4-position.
An aldehyde X in which A3 and A4 stand for H is obtained starting from an aldehyde Hxe2x80x94C(O)xe2x80x94Lxe2x80x94(M)pxe2x80x94CH2xe2x80x94O-THP via the amide of the formula (A1,A2)NC(O)xe2x80x94Lxe2x80x94(M)pxe2x80x94CH2xe2x80x94O-THP and the aminoalcohol of the formula (A1,A2)NCH2xe2x80x94Lxe2x80x94(M)pxe2x80x94CH2OH by oxidation of the latter.
The preparation of some of the starting materials and intermediates referred to above is described in Examples A to G hereinafter.
A) Starting Materials of the Formula HOxe2x80x94Mxe2x80x94C(O)xe2x80x94Q
Aa) A solution of 5.6 ml of 2-fluoroanisole in 60 ml of absolute THF is cooled to xe2x88x9278xc2x0 C. and treated within 15 min. with 31.3 ml of 1.6M butyllithium in hexane. After 15 min. 8.7 g of 1,1,4,7,7-pentamethyldiethylenetriamine are added dropwise and, after a further 2 hrs. at xe2x88x9278xc2x0 C., 9.4 ml of methyl iodide are added dropwise. The mixture is stirred at xe2x88x9278xc2x0 C. overnight, then evaporated and taken up in ether/1N hydrochloric acid. The aqueous phase is extracted with ether and the organic phase is dried over sodium sulphate and evaporated in order to give crude 2-fluoro-3-methyl-anisole. 30 ml of nitrobenzene are cooled in an ice bath and then treated in succession with 8.1 g of aluminium chloride and 11.9 g of 4-bromobenzoyl chloride in 9 ml of nitrobenzene at a maximum 6xc2x0 C. The mixture is stirred and then the 2-fluoro-3-methyl-anisole is added in such a manner that the temperature does not rise above 6xc2x0 C. The solution is left to warm to room temperature overnight, poured into ice-water/ethyl acetate and washed with 10% aqueous sodium chloride solution, dried and concentrated. After chromatography over silica gel with hexane/ether (95/5) as the eluent and crystallization from hexane there are obtained 4.0 g of (4-bromo-phenyl)-(3-fluoro-4-methoxy-2-methyl-phenyl)-methanone, m.p. 93-95xc2x0 C.
Ab) 0.5 ml of oxalyl chloride is added to a solution of 1.2 g of 11-acetylamino-undecanoic acid and 5 drops of DMF in 15 ml of methylene chloride at 0xc2x0 C. and the mixture is stirred at RT for 3 hrs. The solution of the 11-acetylamino-undecanoyl chloride is treated under argon with 0.6 g of 2-fluoroanisole, cooled to xe2x88x9215xc2x0 C. and treated with 1.4 g of aluminium chloride. After 2 hrs. at xe2x88x9215xc2x0 C. the mixture is left to warm to room temperature overnight. The solution is treated with 15 ml of 1M hydrochloric acid at 0xc2x0 C. and then with 20 ml of water. The organic phase is separated and washed with 1M hydrochloric acid, with water and with saturated sodium bicarbonate solution, dried and concentrated. 1.8 g of N-[11-(3-fluoro-4-methoxy-phenyl)-11-oxo-undecyl]acetamide are obtained.
A suspension of 21.1 g of this product in 120 ml of glacial acetic acid and 80 ml of 62% aqueous HBr solution is boiled under reflux, then concentrated and evaporated with toluene. The mixture is dissolved in 240 ml of methylene chloride and 7.3 ml of N-methylmorpholine and peracetylated at 0xc2x0 C. with 6.9 ml of acetic acid and 24.2 g of N-(3-dimethylaminopropyl)-Nxe2x80x2-ethylcarbodiimide hydrochloride. After working up with methylene chloride/0% potassium hydrogen sulphate solution drying of the organic phase and evaporation the residue is dissolved in 150 ml of methanol and stirred at room temperature with 11.1 ml of 5.4M sodium methanolate. The solution is concentrated, taken up in methylene chloride and washed with 8% phosphoric acid solution, saturated sodium bicarbonate solution and 10% sodium chloride solution. After drying there are obtained 17.0 g of N-[11-(3-fluoro-4-hydroxy-phenyl)-11-oxo-undecyl]-acetamide, MS: m/e 337 (M).
B) Starting Material H3Cxe2x80x94Oxe2x80x94Mxe2x80x94C(O)xe2x80x94Q
A solution of 5.4 g of 2,3,5,6-tetrafluoro-anisole in 80 ml of absolute THF is cooled to xe2x88x9278xc2x0 C. and treated with 20.6 ml of 1.6M butyllithium in hexane within 15 min. After 20 min. 7.4 g of 4-bromo-N-methoxy-N-methylbenzamide (prepared from 4-bromo-benzoyl chloride and N,O-dimethylhydoxylamine, hydrochloride with N-methylmorpholine as the base) in 10 ml of THF are added dropwise and the mixture is stirred at xe2x88x9278xc2x0 C. for 2 hrs. The reaction solution is poured into cold 10% potassium hydrogen sulphate solution/ethyl acetate and the organic phase is washed with water and 10% sodium chloride solution and dried. After crystallization from cyclohexane there are obtained 5.8 g of (4-bromo-phenyl)-(2,3,5,6-tetrafluoro-4-methoxy-phenyl)-methanone, m.p. 80-82xc2x0 C.
C) Starting Material H3Cxe2x80x94Oxe2x80x94Mxe2x80x94C(O)xe2x80x94Q
1.45 g of NaSCH3 (95%) are suspended in 80 ml of THF and treated with a solution of 5.51 g of (4-bromo-phenyl)-(2-fluoro-4-methoxy-phenyl)-methanone in 100 ml of THF over a period of 1.5 h. The solution is stirred at RT, again treated with 264 mg of NaSCH3 and stirred for 18 h. The mixture is treated with 50 ml of sat. NH4Cl solution and then 100 ml of sat. NaHCO3 solution. The phases are separated, the inorganic phase is extracted with CH2Cl2 and the organic phase is washed with sat. NaHCO3 solution and with saturated sodium chloride solution and dried. The crude product is purified on silica gel with ethyl acetate:hexane 1:2 as the eluent. 5.88 g of (4-bromo-phenyl)-(4-methoxy-2-methylsulphanyl-phenyl)-methanone are obtained as a yellow oil.
D) Starting Material HOxe2x80x94Mxe2x80x94C(O)xe2x80x94Q
A solution of 52.0 ml of diisopropylamine in 600 ml of THF is treated dropwise at 0xc2x0 C. with 230 ml of 1.6M butyllithium in hexane. After 1.5 hrs. at 0xc2x0 C. the mixture is cooled to xe2x88x9278xc2x0 C. and 26.8 g of 2-fluoro-4-hydroxyacetophenone in 120 ml of THF are added dropwise. After 1 hr. at xe2x88x9278xc2x0 C. 23.7 ml of 3,3-dimethyl-allyl bromide in 24 ml of THF are added dropwise. The mixture is left to warm to room temperature, whereupon 34 ml of acetic acid in 100 ml of ether are sprayed in at xe2x88x9278xc2x0 C. The solution is poured into saturated ammonium chloride solution/ether and washed with 10% sodium chloride solution. After drying and evaporation of the organic phase 33.8 g of 1-(2-fluoro-4-hydroxy-phenyl)-5-methyl-hex-4-en-1-one, m.p. 100-101xc2x0 C., are obtained from ether/pentane.
E) Starting Materials of the Formula HOxe2x80x94Mxe2x80x94Txe2x80x94Q
Ea) A mixture of 2.77 g of 4-hydroxyphenyl-(4-bromo-phenyl)-methanone and 50 ml of hexamethyldisilazane is heated under reflux for 4 h., then concentrated and dried. The resulting 4-trimethylsilyloxyphenyl-(4-bromo-phenyl)-methanone is dissolved in 60 ml of toluene and treated at room temperature under argon with 11 ml of methylmagnesium chloride solution (22% in THF). The mixture is boiled under reflux. After cooling the mixture is treated with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases are washed with saturated sodium chloride solution and dried. After evaporation of the ethyl acetate extracts there are obtained 3.36 g of (RS)-4-[1-(4-bromo-phenyl)-1-hydroxy-ethyl]-phenol, MS: m/e 293 (M+H+, 1Br).
Eb) 30.2 ml of 15% vinylmagnesium chloride solution in THF are added dropwise at 0xc2x0 C. to a solution of 5.58 g of 4-trimethylsilyloxyphenyl-(4-bromo-phenyl)-methanone in 80 ml of toluene. The mixture is stirred at 0xc2x0 C. for 2 h., then at room temperature for 2 h., subsequently hydrolyzed with 40 ml of ammonium chloride solution and extracted with methylene chloride. The extracts are dried, evaporated and purified over silica gel with toluene-acetone as the eluent. There are obtained 2.8 g of (RS)-4-[1-(4-bromo-phenyl)-1-hydroxy-allyl]-phenol, MS: m/e 304 (M+H+, 1Br).
Ec) (RS)4-[1-(4-Bromo-phenyl)-1-hydroxy-cyclopropyl-methyl]-phenol, MS: m/e 300 (M-H2O, 1Br), is obtained analogously to Eb) from a solution of 4-trimethylsilyloxyphenyl-(4-bromo-phenyl)-methanone and cyclopropylmagnesium bromide, which has previously been prepared from bromocyclopropane and magnesium in ether.
Ed) 4 ml of trifluoromethyltrimethylsilane are added to a a solution of 3.1 g of 4-trimethylsilyloxyphenyl-(4-bromo-phenyl)-methanone in 60 ml of THF at 0xc2x0 C. under argon. After stirring at 0xc2x0 C. for 30 min. 69.3 ml of 1M tetrabutylammonium fluoride solution in THF are added dropwise. The reaction mixture is warmed to room temperature and stirred, subsequently treated with 40 ml of water, again stirred and then extracted with methylene chloride. The extracts are washed with saturated sodium chloride solution, dried and evaporated. The crude product is purified over silica gel with toluene/acetone (98:2) as the eluent. 3.0 g of (RS)4-[1-(4-bromo-phenyl)-2,2,2-trifluoro-1-hydroxyl-ethyl]-phenol, MS: m/e 290 (M-CO, 1Br), are obtained.
Ef) 6.6 g of (RS)-4-[1-(4-bromo-phenyl)-1-hydroxy-ethyl]-phenol (Ex. Ea) are dissolved in 50 ml of ethanol, boiled under reflux with 0.34 g of p-toluenesulphonic acid and then evaporated at 30xc2x0 C. The residue is treated with 150 ml of saturated sodium carbonate solution and extracted with ethyl acetate. The organic phases are washed with saturated sodium chloride solution, dried and evaporated. Purification on silica gel with ethyl acetate-hexane (20:80) as the eluent gives 4.1 g of 4-[1-(4-bromo-phenyl)-vinyl]-phenol MS: m/e 274 (M+H+, 1Br).
Eg) A mixture of 457 mg of zinc dust and 692 mg of CuCl in 15 ml of ether is heated under reflux under argon. Subsequently, a solution of 934 mg of [4-[1-(4-bromo-phenyl)-vinyl]-phenoxy]-trimethyl-silane in 15 ml of ether, prepared from 748 mg of 4-[1-(4-bromo-phenyl)-vinyl]-phenol (Ex. Ef) and 14 ml of hexamethyldisilazane under reflux, is added dropwise and thereafter 0.56 ml of methylene iodide is added. The reaction mixture is heated under reflux and diluted with ether. The residue is washed with ether and the filtrate is washed with water, dried and concentrated. The crude product is purified over silica gel with ethyl acetate-hexane as the eluent. 4-(1-(4-Bromo-phenyl)-cyclopropyl)-phenol is obtained as a brown oil, MS: m/e 288 (M+H+, 1Br).
F) The following intermediates are obtained analogously to Example 3 hereinafter:
a) from 3-fluoro-4-hydroxy-acetophenone, (E)-1,4-dibromo-2-butene and N-allyl-methyl-amine there is obtained (E)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-ethanone, MS: m/e 278 (M+H+)
b) from 2-fluoro-4-hydroxy-acetophenone, (E)-1,4-dibromo-2-butene and N-allyl-methyl-amine there is obtained (E)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-2-fluoro-phenyl]-ethanone, MS: m/e 278 (M+H+).
c) from 4-hydroxy-acetophenone, (E)-1,4-dibromo-2-butene and N-allyl-methyl-amine there is obtained (E)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-phenyl]-ethanone, MS: m/e 260 (M+H+)
d) from 1-(2-fluoro-4-hydroxy-phenyl)-5-methyl-hex-4-en-1-one (Ex. D), (E)-1,4-dibromo-2-butene and N-allyl-methyl-amine there is obtained (E)-1-[4-[(E)-4-(allyl-methyl-amino)-but-2-enyloxy]-2-fluoro-phenyl]-5-methyl-4-hexen-1-one, which is converted into the fumarate (1:1), MS: m/e 345 (M)
e) from 1-(2-fluoro-4-hydroxy-phenyl)-5-methyl-hex-4-en-1-one (Ex. D), 1,6-dibromohexane and N-allyl-methyl-amine there is obtained 1-[4-[6-(allyl-methyl-amino)-hexyloxy]-2-fluoro-pheny]-5-methyl-hex-5-en-1-one, which is converted into the fumarate (1:1), MS: m/e 375 (M),
f) From [4-(6-bromo-hexyloxy)-phenyl]-(4-bromo-phenyl)-methanone and 3-aminopropanol there is obtained (4-bromo-phenyl)-[4-[6-[(3-hydroxy-propyl)-amino]-hexyloxy]-phenyl]-methanone, MS: m/e 434 (M+H+, 1Br).
G) 490 mg of 6-(allyl-methyl-amino)-hexan-1-ol (Ex. 42.B) in 5 ml of THF are treated over a period of 1.5 h. with 240 mg of NaH (55-60% dispersion in mineral oil) and with 410 mg of 1-(6-chloro-pyridin-3-yl)-ethanone (Ex. 42.D.a) in 4 ml of THF. The solution is stirred at RT, treated with water and filtered and the residue is washed with methylene chloride. The phases are separated and the inorganic phase is extracted with methylene chloride and then with ethyl acetate. The organic phases are concentrated, taken up in methylene chloride and extracted with 1M HCl. The acidic-aqueous phase is washed with methylene chloride, made basic with NaOH and extracted with methylene chloride. The organic phase is washed with NaHCO3 solution and saturated sodium chloride solution and dried. The crude product is purified on silica gel with methylene chloride:methanol (9:1). 177.8 mg of 1-[6-[6-(allyl-methyl-amino)-hexyloxy]-pyridin-3-yl]-ethanone are obtained as an oil. 176.4 mg of this are converted with 70 mg of fumaric acid into 1-[6-[6-(allyl-methyl-amino)-hexyloxy]pyridin-3-yl]-ethanone-fumarate (1:1), MS: m/e 291 (M+H+).
The invention is also concerned with the compounds of formula I and their salts for use as therapeutically active substances, antimycotically-active and cholesterol-lowering medicaments containing a compound of formula I or a salt thereof as the active ingredient, if desired together with a therapeutically inert carrier, as well as the use of the compounds of formula I and the salts thereof for the production of the aforementioned medicaments.
Cholesterol is a major component of atherosclerotic plaques. The connection between coronary heart disease (CHD) and high LDL cholesterol concentrations in plasma (LDL=low density lipoproteins) and the therapeutic advantage of lowering elevated LDL concentrations are today generally recognized (Gotto et al., Circulation 81, 1990, 1721-1733; Stein et al., Nutr. Metab. Cardiovasc. Dis. 2, 1992, 113-156). Atherosclerotic plaques can grow and lead to occlusion of blood vessels resulting in an ischaemia or an infarct. Studies with respect to primary prophylaxis have shown that a lowering of the LDL concentrations in plasma reduces the frequency of non-fatal incidences of CHD, while the overall morbidity remains unchanged. The lowering of the LDL cholesterol level in plasma of patients with clinically confirmed CHD (secondary intervention) reduces the CHD-mediated mortality and morbidity; the metaanalysis of different studies shows that this decrease is proportional to the reduction of the LDL cholesterol.
The clinical advantage of cholesterol lowering is even greater for patients with confirmed CHD than for asymptomatic persons with hypercholesterolemia. For the majority of patients who had survived a myocardial infarct as well as for patients suffering from angina pectoris or another atherosclerotic disease treatment with a lipid lowering agent is advisable, in which case a LDL cholesterol concentration of 2.6 mmol/l should be striven for.
Preparations such as cholanic acid sequestrating preparations, fibrate, nicotinic acid, probucol as well as the statins (HMG-Co-A reductase inhibitors) such as lovastatin and simvastatin are used for usual standard therapies. A new cholesterol-lowering medicament would be of considerable benefit for CHD patients having a high LDL cholesterol level and in which the striven-for value of 2.5 to 3.0 mmol/l can not be achieved with statins.
Further, the statins have undesired side effects. They inhibit cholesterol production in an early phase of the synthesis cascade, with the formation of non-sterolic isoprenoids also being inhibited. The latter are indispensable for cell functions. The regulation of the cell cycle, the modification of albumins and the transport of electrons in the carbon dioxide chain can therefore be influenced by statins.
For this reason a number of experiments have been undertaken to find plasma-cholesterol lowering medicaments which inhibit the cholesterol synthesis on the one hand after the farnesyl-pyrophosphate stage in order not to inhibit the formation of non-sterolic isoprenoids and on the other hand prior to lanosterol in order to avoid an accumulation of sterol intermediates. The compounds described in European Patent Application No. 636 367, which inhibit 2,3oxidosqualene-lanosterol cyclase (OSC) and which lower the total cholesterol in plasma, belong to these substances.
The present compounds of formula I inhibit cholesterol synthesis and reduce the total cholesterol in plasma. They can therefore be used in the therapy and prophylaxis of hypercholesterolemia, hyperlipemia and arteriosclerosis. In contrast to known compounds they are tolerated better and are more active. Further, they can be used in the therapy of mycoses and hyperproliferative disorders. The following tests were carried out in order to verify the activity of the compounds of formula I and their salts.
Inhibition of Human Liver Microsomal 2,3-Oxidosqualene-lanosterol Cyclase (OSC)
Liver microsomes from a healthy volunteer were prepared in sodium phosphate buffer (pH 7.4). The OSC activity was measured in the same buffer which also contained 1 mM EDTA and 1 mM dithiothreitol. The microsomes were diluted to 0.8 mg/ml protein in cold phosphate buffer. Dry [14C]R,S-monooxidosqualene (MOS; 12.8 mCi/mmol) was diluted to 20 nCi/xcexcl with ethanol and mixed with phosphate buffer-1% BSA (Bovine Serum Albumin). A stock solution of 1 mM test substance in DMSO was diluted to the desired concentration with phosphate buffer-1% BSA. 40 xcexcl of microsomes were mixed with 20 xcexcl of the solution of the test substance and the reaction was subsequently started with 20 xcexcl of the [14C]R,S-MOS solution. The final conditions were: 0.4 mg/ml of microsomal proteins and 30 xcexcl of [14C]R,S-MOS in phosphate buffer, pH 7.4, containing 0.5% albumin, DMSO  less than 0.1% and ethanol  less than 2%, in a total volume of 80 xcexcl.
After 1 hour at 37xc2x0 C. the reaction was stopped by the addition of 0.6 ml of 10% KOH-methanol, 0.7 ml of water and 0.1 ml of hexane:ether (1:1, v/v) which contained 25 xcexcg of non-radioactive MOS and 25 xcexcg of lanosterol as the carrier. After shaking 1 ml of hexane:ether (1:1, v/v) was added to each test tube, these were again shaken and then centrifuged. The upper phase was transferred into a glass test tube, the lower phase was again extracted with hexane:ether and combined with the first extract. The entire extract was evaporated to dryness with nitrogen and the residue was suspended in 50 xcexcl of hexane:ether and applied to a silica gel plate. Chromatographic separation was effected in hexane:ether (1:1, v/v) as the eluent. The Rf values for the MOS substrate and the lanosterol product were 0.91 and, respectively, 0.54. After drying radioactive MOS and lanosterol were observed on the silica gel plate. The ratio of MOS to lanosterol was determined from the radioactive bands in order to determine the OSC inhibition.
The test was carried out on the one hand with a constant test substance concentration of 100 nM and the percentage OSC inhibition against controls was calculated. In addition, the test was carried out with different test substance concentrations and subsequently the IC50 value was calculated, i.e. the concentration required to reduce the conversion of MOS into lanosterol to 50% of the control value. The results are given in the following Table:
Cholesterol Lowering in Fat-fed Hamsters.
Male golden hamsters kept individually were pre-treated for 7 days with a diet containing grated coconut (40 cal. % fat). The animals were then divided into groups each comprising 5 animals. During the treatment the animals were maintained on the same diet. Each test substance was firstly homogenized in 9 ml of water and subsequently mixed with the milled diet. The controls received only feed converted into a paste with water. The animals were treated for 10 days with a test substance dosage of 200 xcexcmol (about 70-120 mg/kg/ay). Blood samples (200 xcexcl) were removed via the jugular vein under light anaesthesia on the last day of the pre-treatment and one day after the last administration of test substance. The plasma cholesterol concentration was determined using a calorimetric enzyme method. The plasma lipoproteins were separated by exclusion chromatography (Hennes et al., Science Tools, 36, 1992, 10-12). The total cholesterol was determined in each fraction using a fluorometric enzyme method (Gamble et al., J. Lipid Res., 19, 1978, 1068-1071) in order to calculate the amount of cholesterol in the LDL and HDL fractions. The activity on plasma cholesterol and LDL and HDL cholesterol, expressed in percent of the control animals, for the products of Examples 8a and 12 is reproduced in the following Table:
As already mentioned, the compounds of formula I and their pharmaceutically acceptable acid addition salts have, moreover, valuable antifungal properties. They are active against a large number of pathogenic fungi which cause topical and systemic infections, such as Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. 
Antifungal Activity In Vitro
The compounds were tested for antifungal activity against Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus using a microdilution method on microtitre plates (96 wells per plate). Yeast supplemented with 1% glucose and 0.25% di-potassium phosphate was used for the three fungal strains. The fungal cells were inoculated at 3xc3x97104 CFU (Colony Forming Unit) in 1 ml of medium per well. The medium contained increasing concentrations of test substance. After incubation at 27xc2x0 C. for 24 or 48 hours the turbidity in each well was measured by a microtitre plate reader. The growth inhibition was calculated in comparison to a control (without test substance). The IC50 value given in the following Table is the concentration of test substance at which the growth is inhibited by 50%.
The compounds of formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.
The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and their pharmaceutically acceptable acid addition salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragxc3xa9es and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants, masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula I can vary within wide limits depending on the pathogenic fungi to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 0.01 g to about 4 g, especially about 0.05 g to about 2 g, comes into consideration for the prevention and control of topical and systemic infections by pathogenic fungi. For cholesterol lowering the daily dosage conveniently amounts to between 1 and 1200 mg, preferably 5 to 100 mg, for adult patients. Depending on the dosage it is convenient to administer the daily dosage in several dosage units.
The pharmaceutical preparations conveniently contain about 1-500 mg, preferably 2-200 mg, of a compound of formula I.